Hypoxia-inducible factor 1 alpha is deregulated by the serum of rats with adjuvant-induced arthritis

Abstract

Rheumatoid arthritis (RA) is known to be associated with increased risks of hypoxia-related diseases, whose progresses are critically determined by HIF-1 alpha, The authors hypothesized that the hypoxia-related complications of RA are associated with HIF-1 alpha deregulation by some factor(s) in RA serum. Arthritis was induced in female Lewis rats by injecting complete Freund`s adjuvant. The effects of arthritic rat serum (ARS) on hypoxic responses were investigated by incubating Hep3B cells in ARS. In the presence of ARS, HIF-1 alpha was down-regulated and inactivated under hypoxic conditions. ARS inactivated AKT and mTOR, which led to impaired HIF-1 alpha protein synthesis. Furthermore, insulin was found to be deficient in ARS and insulin supplementation fully recovered HIF-1 alpha synthesis with AKT and mTOR activation. These results suggest that HIF-1 alpha deregulation by components in serum is responsible for the RA-associated aggravation of hypoxic diseases in extra-articular tissues. (C) 2008 Elsevier Inc. All rights reserved.